Lysosomal storage disorders result from a wide spectrum of genetic mutations affecting proteins integral to normal lysosomal function. Defects in no less than 50 proteins have been documented to cause lysosomal dysfunction, and new proteins linked to lysosomal disease continue to be discovered. Lysosomal diseases are known to affect many tissues and organs with most significantly impacting the brain, leading to severe cognitive impairment including dementia, ataxia, tremors and related motor system dysfunctions, blindness, deafness and other sensory impairments, psychotic episodes and seizures. This complex array of clinical features is reflected in a diversity of underlying molecular and cellular abnormalities, including ectopic dendritogenesis, neuroaxonal dystrophy, protein aggregation conditions including tauopathy, neurodegeneration, and so forth. We believe that this diversity of impact characteristic of storage diseases affecting brain is best explained by looking beyond the lysosome to broader abnormalities in endosomal, retrosomal, autophagosomal, and proteasomal systems, what we refer to as the 'Greater Lysosomal System'. Importantly, there is also increasing evidence that lysosomal diseases are not simply states of storage but are also states of deficiency, with failure to salvage degraded substrates from diseased lysosomes leading to shortages of critical precursors for other metabolic processes. Taken together, this new concept of lysosomal disease stresses the importance of viewing the lysosome and its processing streams not simply as a passive digestive process but rather as an integral player in far reaching cellular events, from signal transduction to homeostatic regulation. In order to advance understanding of lysosomal diseases affecting brain and to illuminate the role of the greater lysosomal system as a metabolic regulator in normal neurons, we propose a series of research aims to test hypotheses that attempt to explain the development of two of the most well documented but enigmatic features of many lysosomal diseases - ectopic dendritogenesis and neuroaxonal dystrophy. Delineation of these pathogenic pathways and the underlying role of the lysosomal system we believe will open the door to understanding, and treating, commoner neurodegenerative diseases that share similar features, from Fragile X and other dendritopathies to dementias like Alzheimer's disease.